The document outlines updates from the ASCO 2019 conference on colorectal cancer treatment strategies, emphasizing discussions on neoadjuvant therapy, the duration of chemotherapy, and the implications of tumor location on treatment outcomes. Key findings indicate that three months of capox is sufficient for most high-risk stage II and low-risk stage III patients, along with advancements in liquid biopsy technology for detecting residual disease. The presentation is led by Dr. Scott Kopetz, a noted expert in the field, highlighting the need for tailored treatment regimens based on individual patient characteristics.

1. ASCO 2019

2. TODAY’S WEBINAR
 SPEAKER(S)
 Scott Kopetz, MD, PhD
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3. RESOURCES
TABOO-TY PODCAST MINI MAGAZINES CLINICAL TRIAL FINDER

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5. ScottKopetz,MD,PhD
Scott Kopetz, MD, PhD, FACP, associate professor, Department of Gastrointestinal
Medical Oncology, Division of Cancer Medicine, The University of Texas MD
Anderson Cancer Center
Dr. Kopetz obtained his residency training in Internal Medicine at Duke University
Medical Center, followed by a medical oncology fellowship at MD Anderson Cancer
Center. He joined MD Anderson Cancer Center in 2006 as an Assistant Professor of
Medicine in the Department of Gastrointestinal Medical Oncology. He subsequently
completed a Ph.D. at MD Anderson in cancer biology with thesis focus on
mechanisms of chemotherapy resistance in colorectal cancer. Dr. Kopetz is board-
certified in Internal Medicine and in Medical Oncology. He has authored over 100
peer-reviewed articles, and is a senior editor for Clinical Cancer Research, and
editorial board member on Journal of Clinical Oncology and JNCI. He is vice chair for
colon cancer research in the NSABP/RTOG cooperative group, and member of the
NIH Gastrointestinal Oncology Steering Committee. In addition, he was a recipient of
peer-reviewed grants from American Society of Clinical Oncology and the National
Institute of Health, among others. He is the principal investigator of several Phase I
and II clinical trials, including the Assessment of Targeted Therapies Against
Colorectal Cancer (ATTACC) study, a novel biomarker enrichment program for
colorectal cancer. His research interests include the biology of refractory colorectal
cancer and the development of novel therapeutics for molecularly distinct subsets
of colorectal cancer patients.

6. MD Anderson
Scott Kopetz, MD, PhD
June 25, 2019
Update from ASCO 2019

7. MD Anderson
• Early stage cancer (stage I-III)
• Neoadjuvant therapy for colon cancer
• Duration of therapy for stage II
• Liquid biopsy for detection of residual disease after surgery
• Advanced cancer : stage IV
• Aggressive chemotherapy
• Treatment for BRAF V600E mutation
• Regorafenib + Nivolumab
Key topics to be discussed
7Update from ASCO 2019

8. FOxTROT:
Presented By Matthew Seymour at 2019 ASCO Annual Meeting

9. Slide 3
Presented By Matthew Seymour at 2019 ASCO Annual Meeting

10. Slide 12
Presented By Matthew Seymour at 2019 ASCO Annual Meeting

11. Slide 11
Presented By Matthew Seymour at 2019 ASCO Annual Meeting

12. Primary outcome: 2-year efficacy
Presented By Matthew Seymour at 2019 ASCO Annual Meeting

13. MD Anderson 13Update from ASCO 2019
Not yet clear if there is a strong advantage to
chemotherapy before colon cancer surgery….
But promising.
• Safe to do
• Shrinks tumors and makes surgery more
successful in removing all the cancer
• We will be doing more of this as standard
practice

14. MD Anderson
• Early stage cancer (stage I-III)
• Neoadjuvant therapy for colon cancer
• Duration of therapy for stage II
• Liquid biopsy for detection of residual disease after surgery
• Advanced cancer : stage IV
• Aggressive chemotherapy
• Treatment for BRAF V600E mutation
• Regorafenib + Nivolumab
Key topics to be discussed
14Update from ASCO 2019

15. Background and rationale (Cont)
•IDEA showed non-inferiority for low risk Stage III colon
cancer (T1-3, N1) treated with 3 months CAPOX1
•Oxaliplatin is associated with cumulative dose-dependent
neurotoxicity
 12.5% grade 3 neuropathy with 6 months of FOLFOX2
15
Timothy J Iveson, MD on behalf of IDEA collaborators
1Grothey et al NEJM 2018
2Andre et al JCO 2009

16. Prospective pooled analysis of four randomised
trials investigating duration of adjuvant oxaliplatin-
based therapy (3 vs 6 months) for patients with
high-risk stage II colorectal cancer:
The IDEA (International Duration Evaluation of
Adjuvant Chemotherapy) Collaboration
Timothy J. Iveson, Alberto F. Sobrero, Takayuki Yoshino, Ioannis Sougklakos, Fang-
Shu Ou, Jeffrey P. Meyers, Qian Shi, Mark P. Saunders, Roberto Labianca, Takeharu
Yamanaka, Ioannis Boukovinas, Niels H. Hollander, Valter Torri, Kentaro Yamazaki,
Vassilis Georgoulias, Sara Lonardi, Andrea Harkin, Gerardo Rosati, James Paul
16Timothy J Iveson, MD on behalf of IDEA collaborators

17. Study Schema
17
Timothy J Iveson, MD on behalf of IDEA collaborators
High risk
Stage II
Colorectal
Cancer
Patients
R
3 months
6 months
Investigator
choice:
FOLFOX or
CAPOX
1:1
FOLFOX: 5FU/LV + Oxaliplatin CAPOX: Capecitabine + Oxaliplatin

18. Definition of High Risk Stage II Disease
• T4
• Poorly differentiated
• Invasion (vascular/lymphatic/perineural)
• Inadequate nodal harvest (<10 SCOT, <12 TOSCA, HORG, ACHIEVE)
• Obstruction
• Perforation
18
Timothy J Iveson, MD on behalf of IDEA collaborators

19. Results: DFS Comparison by Regimen
19
Timothy J Iveson, MD on behalf of IDEA collaborators
0 1 2 3 4 5 6
Years from Randomization
0
10
20
30
40
50
60
70
80
90
100
PercentWithoutEvent
0 1 2 3 4 5 6
Years from Randomization
0
10
20
30
40
50
60
70
80
90
100
PercentWithoutEvent
6 Months
3 Months
Duration
1020 924 810 675 534 357 201
999 906 786 653 504 361 185
0 1 2 3 4 5 6
Years from Randomization
0
10
20
30
40
50
60
70
80
90
100
PercentWithoutEvent
0 1 2 3 4 5 6
Years from Randomization
0
10
20
30
40
50
60
70
80
90
100
PercentWithoutEvent
6 Months
3 Months
Duration
619 569 508 462 404 311 214
635 586 545 503 442 332 220
CAPOX FOLFOX
N Pts
At risk
N Pts
At risk
Duration 5-yr DFS
3m 81.7%
6m 82.0%
Duration 5-yr DFS
3m 79.2%
6m 86.5%
Events/Total
171/1020
159/999
Events/Total
128/619
95/635

20. Conclusions
•Overall non-inferiority not shown for 3 months treatment
for high risk stage II disease
•3 months treatment results in significantly less toxicity
•Similar regimen effect seen as in stage III disease
• Strongly suggests non-inferiority for 3 months CAPOX (vs 6 months
CAPOX)
• Strongly suggests inferiority for 3 months FOLFOX (vs 6 months
FOLFOX)
20
Timothy J Iveson, MD on behalf of IDEA collaborators

21. MD Anderson 21Update from ASCO 2019
Three months of CAPOX is all that is needed for
most patients:
High risk stage II and low risk stage III

22. MD Anderson
• Early stage cancer (stage I-III)
• Neoadjuvant therapy for colon cancer
• Duration of therapy for stage II
• Liquid biopsy for detection of residual disease after surgery
• Advanced cancer : stage IV
• Aggressive chemotherapy
• Treatment for BRAF V600E mutation
• Regorafenib + Nivolumab
Key topics to be discussed
22Update from ASCO 2019

23. Slide 3
Presented By Ryan Corcoran at 2019 ASCO Annual Meeting

24. MD Anderson
Slide 25
Presented By Ryan Corcoran at 2019 ASCO Annual Meeting

25. ctDNA as Prognostic Factor in Stage II/III CRC
Presented By Michael Overman at 2019 ASCO Annual Meeting

26. NRG-GI005: Phase II/III study of ctDNA as a predictive marker for response to adjuvant chemotherapy in patients with stage II colon cancer
Presented By Ryan Corcoran at 2019 ASCO Annual Meeting

27. MD Anderson 27Update from ASCO 2019
Circulating DNA (Liquid Biopsy) may be the next
major advance in detecting and treating CRC
First studies are starting now….

28. MD Anderson
• Early stage cancer (stage I-III)
• Neoadjuvant therapy for colon cancer
• Duration of therapy for stage II
• Liquid biopsy for detection of residual disease after surgery
• Advanced cancer : stage IV
• Aggressive chemotherapy
• Treatment for BRAF V600E mutation
• Regorafenib + Nivolumab
Key topics to be discussed
28Update from ASCO 2019

29. MD Anderson
• Previously: Most patients in the US received one regimen FOLFOX+B
• Currently:
• Depends on goals of care: “Aggressive” combinations to maximize survival
• Depends on tumor location: Right vs Left sided tumors
• Depends on molecular profile
• I have four different regimens that I use routinely depending on answers to
these questions.
• What did we learn at ASCO about this question?
What chemotherapy should be used for newly diagnosed
patients?

30. MD Anderson
• Previously: Most patients in the US received one regimen FOLFOX+B
• Currently:
• Depends on goals of care: “Aggressive” combinations to maximize survival
• Depends on tumor location: Right vs Left sided tumors
• Depends on molecular profile
• I have four different regimens that I use routinely depending on answers to these
questions.
• What did we learn at ASCO about this question?
What chemotherapy should be used for newly diagnosed
patients?

31. MD AndersonMD Anderson
Is there a benefit to triplet chemotherapy?
31Update from ASCO 2019
FOLFOX FOLFIRI
FOLFOXIRI

32. #3508 TRIBE2 Design
32Hanna K. Sanoff, MD
Unresectable met. CRC
≤75 years
ECOG PS 0-1 (0 if 70-75)
No adjuvant oxaliplatin
Randomize
FOLFOX-Bev x 8
N=340
FOLFOXIRI-Bev x 8
N=339
Progression
FOLFIRI-Bev x 8
Progression FOLFOXIRI-bev x85FU-bev maint.
5FU-bev maint.
Primary Endpoint: PFS2
Combination chemo regimens administered for up to 8 cycles (vs TRIBE up to 12)
5FU-bev maint.
5FU-bev maint.

33. Median follow up =
30.6 mos
Arm A
N = 340
Arm B
N = 339
Events, N (%) 217 (64%) 191 (56%)
Median OS, mos 22.6 27.6
HR = 0.81 [95%CI: 0.67-0.98] p=0.033
Overall Survival – preliminary results

34. Absolute INCREASES in Grade ≥3 Toxicity
34
VISNU-1
FFRI vs FOLFOX
% Absolute Increase
TRIBE2
FFRI vs FOLFOX
% Absolute Increase
TRIBE
FFRI vs FOLFIRI
% Absolute Increase
All Grade ≥ 3 15% Nr Nr
Grade ≥ 3 diarrhea 15% 12% 8%
Grade ≥ 3 neutropenia 10% 19% 30%
Grade ≥ 3 asthenia 9% 1% 3%
Grade ≥ 3 mucositis 5% 2% 4%
Treatment-related
mortality 2 more pts nr 2 more pts
*** We have no systematically collected patient reports (PROs) on how this
affects the experience of treatment for mCRC from these trials***
Hanna K. Sanoff, MD

35. Which TRIBE2 Arm is More Patient Centered?
35
FOLFOXIRI-b
Doublet-b
OS 27.6
OS 22.6
1st PFS 12m 2nd line PFS 6.2 m
1st PFS 9.8m 2nd line PFS 5.6m
FOLFIRINOX-b
FOLFOX-b
5FU-b maintenance
FOLFOXIRI
Triplet time: 8 months
Maintenance time: 10.2 months
FOLFOX then FOLFIRI
Doublet time: 8 months
Maintenance time: 7.4 months
VS
5FU-b maint.
Hanna K. Sanoff, MD
FOLFIRINOX-b
FOLFIRI-b

36. MD Anderson
• Previously: Most patients in the US received one regimen FOLFOX+B
• Currently:
• Depends on goals of care: “Aggressive” combinations to maximize survival
• Depends on tumor location: Right vs Left sided tumors
• Depends on molecular profile
• I have four different regimens that I use routinely depending on answers to
these questions.
• What did we learn at ASCO about this question?
What chemotherapy should be used for newly diagnosed
patients?

37. MD Anderson 37Update from ASCO 2019
Triplet chemotherapy may improve outcomes,
but at the cost of moderately increased
toxicities

38. Anatomical and Histological Perspective
Presented By Christopher Lieu at 2019 ASCO Annual Meeting

39. Clinical and Environmental Differences
Presented By Christopher Lieu at 2019 ASCO Annual Meeting

40. Impact of FOLFOXIRI/bev on right-sided mCRC
Presented By Christopher Lieu at 2019 ASCO Annual Meeting

41. MD Anderson 41Update from ASCO 2019
Tumor location may impact outcomes:
Triplet chemotherapy may especially improve
outcomes for patients with right-sided primary
tumors.

42. MD Anderson
• Previously: Most patients in the US received one regimen FOLFOX+B
• Currently:
• Depends on goals of care: “Aggressive” combinations to maximize survival
• Depends on tumor location: Right vs Left sided tumors
• Depends on molecular profile
• I have four different regimens that I use routinely depending on answers to
these questions.
• What did we learn at ASCO about this question?
What chemotherapy should be used for newly diagnosed
patients?

43. MD Anderson
KRAS/NRAS testing: Barriers in dissemination of best-practices
43
KRAS
Tested Not tested
31%
NRAS
Tested Not tested
Median time to obtain testing results: 26 days
Low rate of initial biomarker testing
Flat Iron Health: 13,437 patients with mCRC
from 2013 to 2017, testing with 1st line therapy
Florea et al GI ASCO ‘18
10%
Need for education/awareness

44. ESMO and NCCN Guidelines and Sidedness for RAS wild type patients
Presented By Christopher Lieu at 2019 ASCO Annual Meeting

45. MD Anderson
100
80
60
40
20
0
0 12 24 36 48 60 72 84 96 108
Time From Study Entry, Months
%EventFree
CALGB/SWOG 80405: OS in Left Side
Bevacizumab
32.6
(28.3-36.2)
29.2
(22.4-36.9)
0.88
(0.62-1.25)
*Adjusted for biologic, protocol CT, prior adjuvant therapy, prior RT, age, sex, synchronous disease, in place primary, liver metastases.
Venook A, et al. Presented at: ESMO. 2016.
OS (95% CI), Months HR
(95% CI)Left Right
Cetuximab
39.3
(32.9-42.9)
13.6
(11.3-19.0)
0.55
(0.39-0.79)
p = 0.032 p = 0.036

46. MD Anderson
100
80
60
40
20
0
0 12 24 36 48 60 72 84 96 108
Time From Study Entry, Months
%EventFree
CALGB/SWOG 80405: OS in Right Side
*Adjusted for biologic, protocol CT, prior adjuvant therapy, prior RT, age, sex, synchronous disease, in place primary, liver metastases.
Venook A, et al. Presented at: ESMO. 2016.
Bevacizumab
32.6
(28.3-36.2)
29.2
(22.4-36.9)
0.88
(0.62-1.25)
OS (95% CI), Months HR
(95% CI)Left Right
Cetuximab
39.3
(32.9-42.9)
13.6
(11.3-19.0)
0.55
(0.39-0.79)
p = 0.032 p = 0.036

47. MD Anderson 47Update from ASCO 2019
Tumor location may impact outcomes:
Triplet chemotherapy may especially improve
outcomes for patients with right-sided primary
tumors.
EGFR inhibition with doublet chemotherapy may
improve outcomes for patients with left-sided
primary tumors

48. MD Anderson
BRAF Mutations
48
BRAF mut/
MSS
Jones et al JCO ‘17; Phipps et al Gastroenterology ‘15; Lockhead et al JNCI ’13; Sinicrope ASCO ’14; Tran, et al, Cancer ‘11
Prevalence:
BRAF V600E : 4-6%
Atypical BRAF : 2%
Enrichment:
Right sided, older age
Recommendation:
Test all mCRC patients
V600E
~80%
Poor prognosis of BRAF V600E

49. MD Anderson
BRAF V600E: Impact on Treatment Options
49
Vemurafenib + Cetuximab + Irinotecan
(VIC Regimen)
100%
20%
-100%
0%
-30%
Best%ChangefromBaseline
Cetuximab + Irinotecan
100%
20%
-100%
0%
-30%
Binimetinib + Encorafenib + Cetuximab
Kopetz et al GI ASCO ‘18; Kopetz et al GI ASCO ‘19
Best%ChangefromBaselineBest%ChangefromBaseline
Safety Lead-In
48% RR

50. MD Anderson
Phase 3: Encorafenib + Cetuximab ± Binimetinib in BRAF mutated CRC
50
Arm A - TripletTherapy
Binimetinib + Encorafenib + Cetuximab
n=205
Arm B - DoubletTherapy
Encorafenib + Cetuximab
n=205
Arm C - ControlArm
FOLFIRI + Cetuximab or
irinotecan + Cetuximab
n=205
DISEASE
PROGRESSION
Randomization
DISEASE
PROGRESSION
DISEASE
PROGRESSION
Patient population
• BRAF V600E
mutant
• 1-2 prior regimens
in metastatic setting
n=615
Safety and tolerability will be
assessed in patients
receiving binimetinib,
encorafenib and cetuximab
for the treatment of BRAF
V600E-mutant metastatic
colorectal cancer
n=30
SAFETYLEAD-IN
RANDOMIZED PORTION
Safety and tolerability will be
assessed in patients
receiving binimetinib,
encorafenib and cetuximab
for the treatment of BRAF
V600E-mutant metastatic
colorectal cancer
n=30
Press Release: May 2019
• Primary endpoint of OS was met
• HR 0.60, 95% CI (0.45-0.79), p=0.0003
• Response rate co-primary endpoint was met
• RR of 34% in 2nd and 22% in 3rd line
• vs control arm 2%
Added to
Guidelines

51. MD Anderson 51Update from ASCO 2019
Patients should have their tumor tested for more
than KRAS and NRAS
Novel therapies are available:
BRAF mutation
NTRK fusions
POLE mutations
HER2 amplifications
MSI-High / deficient mismatch repair

52. MD Anderson
• Early stage cancer (stage I-III)
• Neoadjuvant therapy for colon cancer
• Duration of therapy for stage II
• Liquid biopsy for detection of residual disease after surgery
• Advanced cancer : stage IV
• Aggressive chemotherapy
• Treatment for BRAF V600E mutation
• Regorafenib + Nivolumab
Key topics to be discussed
52Update from ASCO 2019

53. MD Anderson
Regorafenib: Approved for all CRC
Combination Strategy for MSS Colorectal Cancer
53Update from ASCO 2019
Nivolumab: Approved for MSI-H CRC
The response rate of either agent alone in microsatellite stable patients is <5%

54. MD Anderson 54

55. MD Anderson 55

56. MD Anderson 56

57. MD Anderson 57Update from ASCO 2019
Keep an eye on this combination
But still needs confirmation in larger studies

58. MD Anderson
• Early stage cancer (stage I-III)
• Neoadjuvant therapy for colon cancer is possible
• Only 3 months of CAPOX is needed for high-risk stage II
• Liquid biopsy for detection of residual disease after surgery is coming
• Advanced cancer : stage IV
• Aggressive chemotherapy is beneficial for a subset of patients, but complex
• New treatments for BRAF V600E tumors
• Regorafenib + Nivolumab looks promising
Key conclusions
58Update from ASCO 2019

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